Dementia is a syndrome characterized with complex cognitive disorders, such as memory loss, degeneration of intelligence, personality changes, abnormal behavior, etc. This syndrome is a cerebral degenerative disease, one of the brain diseases in the central nervous system (CNS). In this syndrome, the continuous apoptosis of neural cells inducing degenerative CNS diseases results in irreversible dysfunctions to the neural network, which leads to permanent damages in corresponding functions of the body. The common characteristic of cerebral degenerative diseases is to induce apoptosis of general or specific cells. However, since there is no regenerative potential in differentiated neural cells, the apoptosis of neural cells results in irreversible impairment of the cerebral functions.
From the facts that the causes of dementia are not elucidated completely and that dementia has various etiological and pathophysiological elements, there is no therapeutic agent for dementia that can be used for peculiar administration. However, it has been known that choline acetyltransferase (ChAT) for synthesizing acetylcholine is reduced to about 20 to 30% in the brain of dementia patients. And also, it has been known that the concentration of acetylcholine, one of the neurotransmitter, is reduced by about 16 to 30%. Therefore, researches for using inhibitors against the cholinesterase which hydrolyzes the neurotransmitter, i.e., acetylcholine, have been carried out as an indirect therapy. The cholinesterase has two forms, i.e., acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The acetylcholinesterase hydrolyzes acetylcholine, one of the neurotransmitters mediating the parasympathetic nervous system, into choline and acetate. The acetylcholinesterase is formed in the endoplasmic reticulum membrane and then moved to the cytoplasmic membrane to perform its function. The enzyme is distributed mainly in cholinergic nerves and their surroundings, especially in the neuromuscular junctions, although it is also found in plasma, liver and other tissues.
Therefore, most of therapeutic agents currently used in Alzheimer's dementia belong to inhibitors against the acetylcholinesterase (i.e., acetylcholine degrading enzymes), which include donepezil (ARICEPT™), rivastigmin (EXELON™), galantamine (REMINYL™). Among the acetylcholinesterase inhibitors, donepezil was approved for patients with dementia by the United States Food and Drug Administration (FDA) in 1996, and is being used for treating mild and moderate or more Alzheimer's dementia. Reversible inhibition of donepezil against the acetylcholine degrading enzymes such as acetylcholinesterase and butyrylcholinesterase increases the amount of acetylcholine in the Alzheimer patients' brains in which the amount of acetylcholine was reduced, thereby activating cholinergic neurons.
As a donepezil-containing formulation, there has been used a tablet form which is orally administered to patients suffering from Alzheimer's dementia. However, it has been reported that the oral formulations of donepezil are impossible to avoid hepatic first-pass effect, thereby being easy to affect liver function. And also, it has been reported that the oral formulation of donepezil makes the active ingredient (i.e., donepezil) exist at high concentration in the gastrointestinal tract, thereby causing gastrointestinal side effects.
And also, patients suffering from fairly advanced dementia have difficulty in taking an oral formulation. To solve this problem, Japanese Patent Publication No. 1999-315016 has disclosed an ointment and a suppository for rectal administration. However, these formulations may not be suitable for administering an active ingredient in a sustained manner over a long period of time, through single administration.
U.S. Patent Publication No. 2004/0258741 and Korean Patent Publication Patent No. 10-2005-0037405 have disclosed a transdermal delivery system obtained by using a synthetic rubber polymer such as styrene-isoprene-styrene (SIS) and/or polyisobutylene (PIB). However, since the transdermal delivery system had relatively low skin penetration rate, it was manufactured so as to have very large area, for overcoming the problem. Therefore, patients' compliance may be decreased at the time when the transdermal delivery system is used to patients for 1 to 2 days through single application. In addition, if the drug concentration in the matrix of the transdermal delivery system is more than 8%, a crystalline solid is formed, which may cause decrease of adhesive force, non-uniform skin penetration rate, and storage problems, thereby being difficult to contain the drug therein in a high concentration.
In addition, U.S. Patent Publication Nos. 2010/0080842, 2008/0138388, and 2009/0175929 have disclosed a transdermal delivery system obtained by using an acrylic pressure-sensitive adhesive having a carboxylic acid functional group or hydroxyl functional groups, as well as using a specific absorption enhancer or a specific crystalline donepezil (a Form-B crystal) or a specific crystallization-inhibiting agent (a (meth)acrylate copolymer having a carboxyl group). However, if an acrylic pressure-sensitive adhesive is used as a matrix of the transdermal delivery system, the drug diffusion is slowed in the pressure-sensitive adhesive layer due to the interaction between donepezil and the acrylic polymer in the layer, which also reduce movement of the drug from the pressure-sensitive adhesive layer to the skin. In order to solve this problem, Korean Patent Publication No. 10-2009-0101667 has disclosed a transdermal delivery system obtained by using an EVA (ethylene vinyl acetate) adhesive and a rosin ester resin as a crystallization-inhibiting agent